Bio-adaptable implantable sensor apparatus and methods

ABSTRACT

Biocompatible implantable sensor apparatus and methods of implantation and use. In one embodiment, the sensor apparatus is an oxygen-based glucose sensor having biocompatibility features that mitigate the host tissue response. In one variant, these features include use of a non-enzymatic membrane over each of the individual analyte detectors so as to preclude contact of the surrounding tissue with the underlying enzyme or other matrix, and mitigate vascularization, and insulation of the various electrodes and associated electrolytic processes of the sensor from the surrounding tissue. In one implementation, the sensor region of the implanted apparatus is configured to interlock or imprint the surrounding tissue so as to promote a high degree of glucose molecule diffusion into the individual detectors, and a constant and predictable sensor to blood vessel interface, yet preclude the tissue from bonding to the sensor, especially over extended periods of implant.

RELATED APPLICATIONS

This application is related to co-owned and co-pending U.S. patentapplication Ser. No. 13/559,475 filed Jul. 26, 2012 entitled “TissueImplantable Sensor With Hermetically Sealed Housing,” Ser. No.14/982,346 filed Dec. 29, 2015 and entitled “Implantable SensorApparatus and Methods”, and Ser. No. 15/170,571 filed Jun. 1, 2016 andentitled “Biocompatible Implantable Sensor Apparatus And Methods”, eachof the foregoing incorporated herein by reference in its entirety. Thisapplication is also related to U.S. patent application Ser. No.10/719,541 filed Nov. 20, 2003, now issued as U.S. Pat. No. 7,336,984and entitled “Membrane and Electrode Structure for Implantable Sensor,”also incorporated herein by reference in its entirety.

GRANT INFORMATION

This invention was made in part with government support under NIH GrantNo. DK-77254. The United States government has certain rights in thisinvention.

COPYRIGHT

A portion of the disclosure of this patent document contains materialthat is subject to copyright protection. The copyright owner has noobjection to the facsimile reproduction by anyone of the patent documentor the patent disclosure, as it appears in the Patent and TrademarkOffice patent files or records, but otherwise reserves all copyrightrights whatsoever.

1. TECHNICAL FIELD

The disclosure relates generally to the field of sensors, therapydevices, implants and other devices which can be used consistent withhuman beings or other living entities for in vivo detection andmeasurement or delivery of various solutes, and in one exemplary aspectto methods and apparatus enabling the use of such sensors and/orelectronic devices for, e.g. monitoring of one or more physiologicalparameters, including through use of a novel membrane structure and/orother components and characteristics.

2. DESCRIPTION OF RELATED TECHNOLOGY

Implantable electronics is a rapidly expanding discipline within themedical arts. Owing in part to great advances in electronics andwireless technology integration, miniaturization, performance, andmaterial biocompatibility, sensors or other types of electronics whichonce were beyond the realm of reasonable use in vivo in a living subjectcan now be surgically implanted within such subjects with minimal effecton the recipient subject, and in fact many inherent benefits.

One particular area of note relates to blood glucose monitoring forsubjects, including those with so-called “type 1” or “type 2” diabetes.As is well known, regulation of blood glucose is impaired in people withdiabetes by: (1) the inability of the pancreas to adequately produce theglucose-regulating hormone insulin; (2) the insensitivity of varioustissues that use insulin to take up glucose; or (3) a combination ofboth of these phenomena. Safe and effective correction of thisdysregulation requires blood glucose monitoring.

Currently, glucose monitoring in the diabetic population is basedlargely on collecting blood by “fingersticking” and determining itsglucose concentration by conventional assay. This procedure has severaldisadvantages, including: (1) the discomfort associated with theprocedure, which should be performed repeatedly each day; (2) the nearimpossibility of sufficiently frequent sampling (some blood glucoseexcursions require sampling every 20 minutes, or more frequently, toaccurately treat); and (3) the requirement that the user initiate bloodcollection, which precludes warning strategies that rely on automaticearly detection. Using the extant fingersticking procedure, the frequentsampling regimen that would be most medically beneficial cannot berealistically expected of even the most committed patients, andautomatic sampling, which would be especially useful during periods ofsleep, is not available.

Implantable glucose sensors have long been considered as an alternativeto intermittent monitoring of blood glucose levels by the fingerstickmethod of sample collection. These devices may be fully implanted, whereall components of the system reside within the body and there are nothrough-the-skin (i.e. percutaneous) elements, or they may be partiallyimplanted, where certain components reside within the body but arephysically connected to additional components external to the body viaone or more percutaneous elements. The operability of one such fullyimplanted sensor has been demonstrated as a central venous implant indogs (Armour et al., Diabetes, 39:1519 1526 (1990), incorporated hereinby reference in its entirety). Although this sensor provided directrecording of blood glucose, which is most advantageous for clinicalapplications, the described implantation at a central venous site posesseveral risks and drawbacks, including risk of blood clot formation andvascular wall damage. An alternative that does not present such risks tothe user is to implant the sensor in a “solid” tissue site and to relatethe resulting signal to blood glucose concentration.

Typical sensors implanted in solid tissue sites measure theconcentration of solutes, such as glucose, in the blood perfusing themicrocirculation in the vicinity of the sensor. Glucose diffuses fromnearby capillaries to the sensor surface. Because such diffusion occurseffectively only over very small distances, the sensor responds to thesubstrate supply only from nearby blood vessels. Conversely, solutesthat are generated in the locality of the sensor may be transported awayfrom the sensor's immediate vicinity by the local microvasculature. Ineither case, access to and/or association with the localmicrocirculation may influence the sensor's response.

Optical glucose sensors are known in the prior art. Schultz and Mansouridisclosed one such version of an optical sensor (J. S. Schultz and S.Mansouri, “Optical Fiber Affinity Sensors,” Methods in Enzymology, K.Mosbach, Ed., Academic Press, New York, 1988, vol. 137, pp. 349-366). Avariety of other optical techniques including optical coherencetomography, near infrared spectroscopy, Raman spectroscopy, andpolarimetry have been tried and failed. Light-based systems using eitherabsorption of light, or emission of light when glucose is “excited” bylight have not proven to be accurate since there is no specific lightabsorption or emission spectrum for glucose. Furthermore, numerous otherchemicals or interfering substances in the blood overlap in spectrumwith glucose, causing optical methods to be insufficiently specific forglucose monitoring.

A number of electrochemical glucose sensors have also been developed,most of which are based on the reaction catalyzed by the enzyme glucoseoxidase. One such configuration involves the use of glucose oxidase tocatalyze the reaction between glucose and oxygen to yield gluconate andhydrogen peroxide. The hydrogen peroxide is either detected directly, orcan be further decomposed by a second enzyme, e.g. catalase, in whichcase the sensor measures oxygen consumption. In order for glucoseoxidase based sensors to function properly, the presence, in thevicinity of the enzyme, of excess molecular oxygen relative to molecularglucose is necessary. However, this requirement gives rise to a sensordesign problem related to “oxygen deficit,” since the concentration ofoxygen in bodily tissues is significantly less than that of glucose.

For example, the typical concentration of glucose in the blood is about4 to about 20 mM, whereas a typical concentration of oxygen in bloodplasma may be only about 0.05 to about 0.1 mM. Oxygen concentrations inother tissue fluids may be even lower. As the chemical reaction, andthus, the sensor signal, is limited by the reactant that is present inthe sensor's reaction zone at the lowest concentration, an implantedsensor of simple construction would remain limited by oxygen, and wouldtherefore be insensitive to the metabolite of interest (e.g. glucose).Thus, there is a need for differential control of the permeability ofthe sensor diffusion device (e.g., “membrane”) to restrict or modulatethe flux of the metabolite of interest (e.g. glucose), and provide astoichiometric equivalent or excess of oxygen in the reaction zone. Thesensor incorporating such a membrane can then be sensitive to themetabolite of interest over the physiologic range. Also, for successfulfunctioning of the implanted sensor, the membrane material exposed tothe bodily tissue must further be biocompatible, or elicit a favorableresponse from the body. Several membrane solutions have been proposed todate.

One such solution has been through the use of macroporous or microporousmembranes to ratio the diffusion of oxygen and glucose to the sensingelements, such as that set forth in U.S. Pat. No. 4,759,828 to Young,which discloses use of a laminated membrane with an outer microporousmembrane having a pore size of 10 to 125 A (Angstrom) to limit thediffusion of glucose molecules. However, one problem with the use of amacroporous or microporous membrane relates to exposure of the sensingelement of the sensor to the environment of the body, which can resultin “fouling” or other deleterious effects. Another solution is disclosedin U.S. Pat. No. 4,671,288 to Gough, which describes a cylindricaldevice, implantable in an artery or vein, which is permeable to glucoseonly at an end of the device, and with both the curved surface and endpermeable to oxygen. In vascular applications, the advantage is directaccess to blood glucose, leading to a relatively rapid response.However, a major disadvantage of vascular implantation is thepossibility of eliciting blood clots or vascular wall damage, as notedsupra.

U.S. Pat. No. 5,660,163 to Schulman discloses another solution throughuse of a silicone rubber membrane containing at least one “pocket”filled with glucose oxidase in a gelatinous glucose- andoxygen-permeable material located over a first working electrode, suchthat the length of the “pocket” is a multiple of its thickness tooptimize the linearity between current and the glucose concentrationmeasurement. However, because the long axis of the “pocket” is orientedparallel to the electrode surface, this design may be less amenable tominiaturization for tissue implantation, and may suffer from yet otherdisabilities relating thereto.

Still further, another solution has been to utilize a composite membranethat is hydrophilic and also contains small hydrophobic domains toincrease the membrane's overall gas solubility, giving rise todifferential permeability of glucose and oxygen (e.g. U.S. Pat. Nos.4,484,987 and 4,890,620 to Gough). However, one salient disadvantage ofthis approach relates to the requirement that the amount of hydrophobicpolymer phase must be relatively large to allow for adequate oxygenpermeability. This substantially reduces the hydrophilic volumeavailable for enzyme inclusion sufficient to counter inactivation duringlong-term operation.

Another alternative is described in U.S. Pat. No. 4,650,547 to Gough,which discloses a “stratified” structure in which the electrode wasfirst overlaid with an enzyme-containing layer, and second with anon-glucose-permeable membrane. The resulting structure is permeable tooxygen over a large portion of the surface of the membrane, whereasglucose can only reach the enzyme through the “edge” of the device, thusregulating access of the reactants to the enzyme.

A significant concern in the context of e.g., implantable solid tissuedevices is the so-called “tissue response”, wherein the host'sphysiology proximate to the implanted sensor is irritated or adverselystimulated into an antibody-modulated or other response which can bedeleterious to the operation of the implanted device, especially overlonger periods of time. The process of implantation (i.e., creation of awound) and the presence of a device (i.e., a foreign body) within livingtissue cause early host reactions (e.g., within two to four weeks ofimplantation) that generally include: (i) blood-biomaterial interaction,(ii) provisional matrix formation, (iii) acute inflammation, (iv)chronic inflammation, (v) foreign body reaction (FBR), and (vi)fibrosis/fibrous capsule development (Anderson, James. “BiologicalResponses to Materials.” Annu. Rev. Mater. Res. 31(2001): 81-110.). Eachof these phases of wound healing has a cascade effect, including releaseof specific bio-chemicals (e.g., mitogens, chemoattractants, cytokines,growth factors, etc.) and migration of specific wound healing-associatedcells (e.g., neutrophils, macrophages, fibroblasts, foreign body giantcells, etc.) to the implant site, which leads to subsequent phases, andeventually adaptation to or rejection of the implanted device.

In some cases, although the living tissue adapts to the implanteddevice, the wound healing process may render the device non-functional(or at very least reduce its functionality and/or accuracy), therebynegating any benefit to the patient. For example, in implanted devicesthat depend on diffusive transport of solutes to or from the bloodstream(e.g. implanted chemical sensors), such responses can negatively impactdevice operation due to an increase in mass transfer resistance betweenthe bloodstream and active portions of the device surface resulting froman FBR-mediated development of fibrous tissue surrounding the device.The FBR also can complicate explants of the implanted device (due to,e.g., the FBR causing significant encapsulation of the implanted device,thereby increasing its effective size when explanted), and result in yetother disabilities. Thus, accounting for (and minimizing) the FBRremains an important consideration for nearly all implanted devices.Some prior art solutions for implantable sensors have attempted to uselayers external to the sensing enzyme region to actively modulate oreliminate the FBR. Such approaches have typically used materials forsuch layer(s) which are designed to encourage blood vessel growth andperfusion in the vicinity of the sensor or into the layer(s), which isundesirable, because such modulated responses are often not predictableand furthermore may not be sustainable for extended durations.

An illustration of the final phases of a typical wound healing 100response are depicted in the example of FIG.1, showing an implantedobject 102 and surrounding host tissue 104. In the FBR phase 106 ofwound healing, tissue repair cells 108 (e.g., macrophages, foreign bodygiant cells, etc.) are recruited to the surface of the object 102 andthe surrounding tissue 104. Subsequently, in the fibrosis phase 110, theobject 102 undergoes fibrous encapsulation by granulation tissue and/orconnective tissue 112.

Biocompatibility of a medical device, such as e.g., an implantablesensor, may be defined as the ability of the device to perform asintended with an appropriate host wound healing response, whileminimizing the magnitude and duration of the wound healing response.Factors that affect biocompatibility may include, inter alia, extent ofinjury (e.g., amount of tissue removal, size of incision, etc.)resulting from the implantation process, integrity of basement membranestructures during and after implantation, material compositions of thedevice, surface properties of the device, dimensions of the device,exposure of tissues to electrical and/or chemical components (includingbyproducts) of the device, motion and/or migration of the device in theimplant site, and ability to function under at least a minimal degree ofgranulation tissue formation, FBR, and fibrosis.

Traditionally, “solid tissue” sensors (including the aforementionedglucose sensors) are implanted within the living subject at a generallysuperficial layer or level of the tissue, so as to (i) mitigate tissuetrauma resulting from the surgical implantation procedure, and (ii)mitigate interference from interposed solid tissue to the propagation ofelectromagnetic radiation (e.g., wireless transmissions to and from theimplant). Specifically, historically larger implants require a largervolume within the solid tissue of the recipient, and hence placing thelarger implant further down into the layers of tissue, etc. residingbelow the epidermis requires a larger incision, possibly includingthrough various blood vessels, basement membranes, and/or other featuresand possibly requiring removal of some solid tissue to accommodate thevolume of the implant, thereby likely extending duration and intensitythe host's wound healing response.

Further, some sensors may expose the host tissue to harmful chemicals orcompounds that increase perturbation of host tissue and reaction of thetissue to the implant. In one specific example, some conventionalglucose sensors monitor glucose via detection of hydrogen peroxide,which is a product of glucose reaction with oxygen catalyzed by theglucose oxidase (GOx) enzyme. Hydrogen peroxide is widely regarded as acytotoxic agent that can lead to cell death and tissue necrosis inexcess concentrations, both of which stimulate the wound healingresponse. In another example, some glucose sensors (peroxide-based orotherwise) may be configured such that enzyme-embedded membranes aredirectly exposed to the host blood and tissue, which may trigger animmunogenic response. In even another example, some implants may becomprised of materials that increase duration and/or intensity of woundhealing.

Likewise, electrical circuitry and/or electrochemical processesassociated with an implanted or partly implanted device may trigger asimilar immunogenic response in the host. For instance, electricalcurrents and potentials associated with an electrolytic sensor can, ifsufficiently proximate to the host's tissue, induce varying degrees ofthe aforementioned tissue response, which is likewise undesired.

Additionally, motion and/or migration of an implanted device mayexacerbate the chronic inflammation phase of wound healing. Prolongedchronic inflammation is also associated with increased FBR and fibrosis,and may lead to implant rejection and require extraction or “explant”(i.e., removal of the sensor). The explant process generally becomesmore difficult and traumatic to the tissue if there is significant FBRand fibrosis, which may cause tissue to responsively grow connectivetissue around the implanted sensor over time.

It is recognized that at least minimal levels of FBR and fibrosis (i.e.,end stages of tissue response) are normal to the wound healing process.The FBR is characterized by the formation of foreign body giant cells,which adhere to surfaces of the device and stimulate fibrosis (i.e.,encapsulation by fibrous connective tissue with a decreased density ofcapillary blood vessels relative to undisturbed tissue) of the device inan attempt to isolate the implant and FBR from the local tissueenvironment. The materials, form, and topography of the surface of theimplanted device, as well as the degree and duration of previous stagesof wound healing may all effect the FBR and fibrosis processes. When theFBR is minimized, there is generally increased regeneration of normaltissue, and replacement of tissue by the fibrous capsule is decreased.In some conventional implanted sensors, even normal degrees of FBR andfibrosis may obstruct the sensing components, thereby rendering thedevice non-functional and necessitating replacement (i.e., explant ofthe current device and implant of a new device), which may reinitiatethe wound healing process.

Moreover, blood vessel vascularization and “ingrowth” into portions ofan implanted device (such as an implanted sensor) may occur in certainprior art applications, effectively bonding the device (at least incertain areas) to the host, thereby precluding a clean separation of thedevice from the surrounding FBR-induced encapsulation during deviceexplant. Some prior art solutions for implantable sensors have attemptedto use layers external to the sensing enzyme region to actively modulateor eliminate the FBR; see, e.g., U.S. Pat. No. 6,558,321 to Burd, et al.entitled “Systems and methods for remote monitoring and modulation ofmedical devices,” which describes use of a porous material on theexterior of the sensor's enzyme membrane element. Such approaches havetypically used materials for such layer(s) which are designed toencourage blood vessel growth and perfusion in the vicinity of thesensor or into the layer(s), which is undesirable, because suchmodulated responses are often not predictable and furthermore may not besustainable for extended durations.

Accuracy is also an important consideration for implanted analytesensors, especially in the context of blood glucose monitoring. Hence,ensuring accurate measurement for extended periods of time (andminimizing the need for any other confirmatory or similar analyses) isof great significance. The response and accuracy of conventional sensorscan be adversely affected by FBR or other tissue response in the regionof the analyte sensor as noted above; this effect can be exacerbated thelonger the sensor is left implanted. Specifically, as the FBR or tissueresponse proceeds over time, the mechanical relationship between animplanted sensor device and the host's tissue in the immediate area ofimplantation (including micro-perfusion within blood vessels adjacent tothe sensor) can significantly change due to movement between the tissue(and the microvascular structures therein which provide communicationbetween the device and the body's circulatory system) and the devicesurface, thereby potentially degrading the accuracy and/or reliabilityof the sensor device. Notwithstanding, the host tissue needs to bemaintained in close physical contact with the detector or sensor of theimplanted device, in order for the sensor to operate properly (e.g., theblood glucose molecules to migrate into the sensor for utilizationtherein). Hence, there is somewhat of a “catch-22” involved; anyeffective sensor will need to be implanted at a site with sufficientavailable blood glucose (delivered via blood vessels or microvasculatureof the host in that area) and maintain close physical contact with thetissue at that site for proper and accurate sensor operation, yet suchclose contact (including even the act of implantation) can trigger atissue response which can be deleterious to the accuracy and operationof the sensor. Sensors relying on the diffusion of glucose areparticularly susceptible to variations in tissue response andencapsulation, since these factors directly affect the rate andmagnitude of glucose diffusion from the capillaries to the implantedsensor element.

Lastly, many conventional implantable devices are sufficient only forrelatively short-term implantation due to expiration or exhaustion ofone or more components of the device (as well as the aforementioneddegradation of accuracy/response due to effects of the FBR). In thiscase, similar to devices obstructed by FBR and fibrosis, the devices maynecessitate frequent replacement (i.e., explant of the current deviceand implant of a new device), which may reinitiate the wound healingprocess.

As such, there is a compelling need for an implantable biocompatibleanalyte sensor designed to operate accurately over extended periods ofimplantation, while decreasing the duration and/or intensity of woundhealing responses from the host (including biocompatibility featuresthat avoid the foregoing disabilities and drawbacks associated withprior art implantable devices), as well as techniques for operating thesensor so as to enhance its performance and longevity/viability withinthe host being.

SUMMARY

The present disclosure satisfies the foregoing needs by providing, interalia, improved implantable apparatus for accurately sensing analytelevels within a living subject, including for extended periods of timewithout explant, and methods of operating the same.

In one aspect, an implantable analyte sensor is disclosed. In oneembodiment, the sensor includes: a biocompatible housing having a sizeand shape suitable for implantation in a body; a plurality of analytedetectors; circuitry operatively connected to the plurality of detectorsand configured to process at least a portion of signals generated by oneor more of the detectors to produce processed signals; data transmissionapparatus configured to transmit at least a portion of the processedsignals to a receiver (whether inside the body, outside of the body, orcombinations thereof) when the implanted sensor is disposed in a tissueenvironment within the body; and an electrical power source operativelycoupled to at least the circuitry and data transmission apparatus andconfigured to provide electrical power thereto. In one variant, thesensor further comprises apparatus configured to promote interlock of atleast a portion of the plurality of detectors with biological tissue ofthe body proximate thereto without substantive blood vessel ingrowth.

In one implementation, the analyte comprises blood glucose, and theapparatus configured to promote interlock comprises at least onemembrane configured for direct contact with the biological tissue afterimplantation of the sensor, the at least one membrane at least partlypermeable to diffusion of the blood glucose therethrough, yet which isconfigured to frustrate the blood vessel ingrowth.

In another embodiment, the sensor includes: a biocompatible housinghaving a size and shape suitable for implantation in a body; a pluralityof analyte detectors; circuitry operatively connected to the pluralityof detectors and configured to process at least a portion of signalsgenerated by one or more of the detectors to produce processed signals;data transmission apparatus configured to transmit at least a portion ofthe processed signals to a receiver when the implanted sensor isdisposed in a tissue environment within the body; and an electricalpower source operatively coupled to at least the circuitry and datatransmission apparatus and configured to provide electrical powerthereto. The sensor is configured to not stimulate blood vesselvascularization at least proximate to the plurality of detectors, yetpermit diffusion of the analyte (e.g., glucose) into the plurality ofdetectors.

In yet another embodiment, the sensor includes: a biocompatible housinghaving a size and shape suitable for implantation in a body; a pluralityof analyte detectors; circuitry operatively connected to the pluralityof detectors and configured to process at least a portion of signalsgenerated by one or more of the detectors to produce processed signals;data transmission apparatus configured to transmit at least a portion ofthe processed signals to a receiver when the implanted sensor isdisposed in a tissue environment within the body; and an electricalpower source operatively coupled to at least the circuitry and datatransmission apparatus and configured to provide electrical powerthereto. The circuitry is configured such that at least a portion of theplurality of detectors are able to adapt for variations in a biophysicalinterface between the detectors and biological tissue of the body overtime, the variations caused at least in part by biological processeswithin the body.

In another aspect, a method of configuring an implantable sensing deviceso as to limit tissue response from a living host in which the device isultimately implanted is disclosed. In one embodiment, the methodincludes configuring the sensing device to facilitate contact of atleast one outer membrane thereof with tissue of the living host when thedevice is implanted, the facilitating contact comprising (i) enablingtissue response by the living host to substantially cover or encase atleast a portion of the at least one outer membrane; and (ii) notencouraging or avoiding vascularization by the living host into the atleast one outer membrane.

In one variant, the implantable sensor comprises a glucose sensor, andthe enabling tissue response comprises configuring the sensing devicesuch that it is in direct physical contact with the tissue of the livinghost when implanted so as to facilitate migration of at least bloodglucose molecules to the at least one outer membrane, and the notencouraging vascularization comprises configuring the at least one outermembrane to have a pore size on at least an outer surface thereofsufficient to inhibit the vascularization.

In another aspect, a method of maintaining a position and orientation ofan implantable sensor within a living host while also maintaining itsoperability is disclosed. In one embodiment, the sensor includes asensing feature for sensing an analyte (e.g., glucose), and the methodincludes: implanting the sensor within a location of the host; enablinga tissue response to the implanted sensor such that tissue of the hostproximate the implanted sensor substantially interlocks with the sensingfeature; and frustrating vascularization of the tissue into the sensingfeature. The substantial interlock with the sensing feature providesmechanical stability to the sensor so as to maintain the position andorientation, minimizing movement between the sensor surface and thetissue adjacent to the sensor without causing any significant “bonding”of the tissue to the sensing feature or sensor body. Minimizing thepotential for relative movement or slippage between the sensor surfaceand the adjacent tissue helps ensure stability of the sensor responsecharacteristics and also avoids exacerbating the FBR frommechanically-induced fibrotic response effects.

In another aspect, a miniaturized biocompatible implantable sensor isdisclosed. In one embodiment, the sensor comprises a plurality ofoxygen-based glucose sensing elements disposed on a sensing regionthereof, and is fabricated from biocompatible materials and usesbiocompatible processes for sensing which advantageously mitigate oreliminate physiological responses from the host (e.g., chronicinflammation, FBR, blood vessel in-growth, and/or fibrosis), while alsoenabling close physical contact with the host's tissue so as to permitlong-term, accurate blood glucose monitoring and easy subsequent explantof the sensor.

In one variant, the sensor is further configured to dynamicallyaccommodate any tissue changes which do occur, algorithmically (e.g.,within the control logic of the device). In one particularimplementation, the miniaturized size, optimized materials andconstruction, and adaptive operation of the sensor apparatus enable,inter alia, deeper and less traumatic implantation within the host'ssolid tissue (and subsequent extraction) and continued operation withinthe host for extended periods of time, thereby providing all of thebenefits of an implantable sensor without the attendant disabilities ofboth prior art implantable devices and associated techniques.

In a further aspect, a method of extending the in vivo operatinglifetime of an implantable electronic device is disclosed. In oneembodiment, the method includes controlling a level of tissue responseand blood vessel vascularization from a host being over time such thatclose contact between the solid tissue of the host and a sensing regionof the implantable device is achieved, yet simultaneously mitigatingvascularization into the sensing region and encapsulation of at leastthe remainder of the sensing apparatus. In one variant, the foregoingcontrol is accomplished via coordination of a plurality of configurationfactors, including: (i) electrical insulation of the solid tissue in atleast the sensing region of the device, (ii) enzyme insulation of thesolid tissue in at least the sensing region of the device; (iii) use ofan outer anti-vascularization sensor barrier for at least some of thesensors in the sensing region, and (iv) use of substantially smooth,biocompatible materials for portions of the device outside of thesensing region.

In yet another aspect, a method of implantation is disclosed. In oneembodiment, the method includes implanting a sensor apparatus having asensing region configuration in a living subject so as to mitigate FBRand adhesion of the tissue to the sensing region, and create atopological “imprint” in three dimensions, and then subsequentlyexplanting the sensor apparatus and implanting a replacement sensorapparatus (or the explanted apparatus that has been refitted orrefurbished) with the same or similar sensing region configuration inthe same location, and utilizing the same imprint for the sensing regionthereof.

In a further aspect, a surgical method is disclosed. In one embodiment,the method includes: implanting a sensor apparatus having a sensingregion configuration in a living subject, the sensor apparatusconfigured to mitigate adhesion of the tissue to the sensing regionresulting from a body response; and substantially immobilizing thesensor apparatus within the living subject as part of the implanting. Inone implementation, the implanting and immobilizing enable creation of atopological imprint feature in three dimensions, the imprint feature andthe mitigated adhesion cooperating to enable subsequent explanting ofthe sensor apparatus and implanting a replacement sensor apparatushaving a substantially similar sensing region configuration utilizingthe same imprint feature for the sensing region thereof.

Other features and advantages of the present disclosure will immediatelybe recognized by persons of ordinary skill in the art with reference tothe attached drawings and detailed description of exemplary embodimentsas given below.

BRIEF DESCRIPTION OF THE DRAWINGS

FIG. 1 is an illustration of foreign body response and fibrosis phasesof a typical wound healing response that may occur after implantation ofan object or device.

FIG. 2 is a front perspective view of one exemplary embodiment of afully implantable biocompatible sensor apparatus according to thepresent disclosure.

FIGS. 2A-2C are top, bottom, and side elevation views, respectively, ofthe exemplary sensor apparatus of FIG. 2.

FIG. 3 is a side cross-sectional view of one exemplary detector elementof a detector array in a fully implantable sensor apparatus according tothe present disclosure.

FIG. 3A is a side cross-sectional view of one exemplary spout region(outer non-enzyme membrane removed) of a detector element of a detectorarray in a fully implantable sensor apparatus according to oneembodiment of the present disclosure.

FIG. 4 is side cross-sectional view of an exemplary sensor apparatusimplanted within a cavity or pocket formed in the tissue of the host,and proximate to the muscular fascia thereof.

FIG. 5 is a side cross-sectional detail view of a detector element ofthe sensor apparatus of FIGS. 2-3A, illustrating the “interlocking” oftissue/tissue response therewith after implantation as in FIG. 4.

FIG. 6 herein is a plot of “proximity index” vs. average sensor O₂ levelat 12 weeks (implanted duration) obtained during clinical trials by theAssignee hereof using an exemplary sensor device similar to that of FIG.2.

FIG. 7 is a generalized logical flow diagram illustrating an exemplaryembodiment of a method of surgical implantation leveraging tissue“imprint” according to the present disclosure.

All Figures © Copyright 2015-2016 GlySens Incorporated. All rightsreserved.

DETAILED DESCRIPTION

Reference is now made to the drawings, wherein like numerals refer tolike parts throughout.

Overview

In one exemplary aspect, the present disclosure provides afully-implantable sensor apparatus that is particularly adapted to bothutilize and mitigate tissue response, thereby enabling accurate in vivooperation over long durations. It is recognized by the inventors hereofthat such tissue response cannot be completely eliminated; hence, themethods and apparatus of the present disclosure make advantageous use ofthe tissue response (i.e., to promote a high degree of stable contactwith a sensing region of the sensor apparatus—in effect creating an“imprint” of the sensing region on the host's tissue), yet alsosimultaneously mitigate unwanted tissue response includingvascularization and significant encapsulation, each of which canadversely impact the operation of the sensor apparatus over time, andmake the sensor apparatus difficult to explant (and hence create moretissue trauma within the host).

In one variant, the sensor apparatus is a miniaturized somewhat planaroxygen-based, biocompatible glucose sensor with multiple (e.g., 8)individual sensor elements disposed in a common sensing region on oneside of the housing. The apparatus may be implanted within the host'storso (e.g., subcutaneous and proximate to the extant abdominal musclefascia), and oriented so that the sensing region faces away from theskin surface (e.g., the plane of the sensor is substantially parallel tothe fascia and the epidermis/dermis, with the sensing region facinginward toward the musculature under the fascia) and in direct contactwith the solid tissue of the host, for inter alia close contact withblood-rich tissues and substantial mechanical stability.

The sensor apparatus include biocompatibility features that limit ormitigate the host tissue response to implantation and the presence ofthe foreign body within the host for extended periods. In oneimplementation, these features include: (i) use of a low-porositynon-enzymatic membrane over each of the individual sensor elements ordetectors so as to preclude contact of the surrounding host solid tissuewith the underlying enzyme matrix (and also potentially between the hosttissue and reaction byproducts), and simultaneously frustrate oreliminate vascularization; (ii) insulation of the various electrodes andassociated electrochemical processes of the sensor from the surroundinghost solid tissue so as to mitigate any tissue response due toelectrical currents or potentials generated by the individual detectors;(iii) use of a non-agitating (e.g., non-peroxide) based enzyme matrixmaterial for analyte detection; (iv) use of biocompatible materials forthe housing and other components of the sensor apparatus; (v) use ofanti-migration features such as anchors or tethers, as well as the shapeand implantation placement of the device; and/or (vi) reduction of thesize of the implanted apparatus.

Concurrently, the sensor region of the apparatus is sized and shaped tofacilitate a high degree of contact with blood-carrying solid tissue ofthe host at the implantation site, thereby facilitating ready (andconsistent) migration of blood glucose molecules into the individualdetectors of the sensor apparatus, and promoting physical interlock withthe solid tissue (and subsequent tissue response) of the host.

In practice, the exemplary sensor apparatus provides excellent andreliable contact (and hence analyte migration and subsequent sensing)with the host's solid tissue at the implantation site, yet avoidsvascularization and its attendant problems, and avoids exacerbatingfibrous encapsulation of the apparatus, thereby facilitating longer-termoperation in vivo, and easier (and less traumatic) subsequent explant.

The exemplary implementation of the foregoing biocompatible sensorapparatus is also advantageously suitable for “long-term” implantation(e.g., 12-18 months) by virtue of its design and operation, therebydecreasing reoccurrence of injury and repeated inducement of the woundhealing response necessitated by expiration and replacement of thedevice, which can be performed on an outpatient basis by a clinicianusing only local anesthetic and recovery time from the procedure isminimal.

Moreover, the foregoing imprint created by the sensor apparatus can beadvantageously re-used (whether by a subsequent replacement sensor ofthe same or similar configuration, or the same sensor apparatus that hasbeen e.g., refitted with a new battery), so that the foreign bodyresponse or other deleterious host responses are yet further avoided,and trauma to the host is minimized.

The aforementioned implementation may include one or more features thatdynamically adapt operation of the sensor apparatus to the host's tissueresponse over time, leveraging the observation that any non-mitigatedresponse can be accounted for by the sensor apparatus, such as viasignal processing either within, or off-board from, the sensor apparatuswhile implanted.

Detailed Description of Exemplary Embodiments

Exemplary embodiments of the present disclosure are now described indetail. While these embodiments are primarily discussed in the contextof a fully implantable glucose sensor, such as those exemplaryembodiments described herein, and/or those set forth in U.S. Pat. No.7,894,870 to Lucisano et al. issued Feb. 22, 2011 and entitled “Hermeticimplantable sensor;” U.S. Patent Application Publication No. 20110137142to Lucisano et al. published Jun. 9, 2011 and entitled “HermeticImplantable Sensor;” U.S. Pat. No. 8,763,245 to Lucisano et al. issuedJul. 1, 2014 and entitled “Hermetic feedthrough assembly for ceramicbody;” U.S. Patent Application Publication No. 20140309510 to Lucisanoet al. published Oct. 16, 2014 and entitled “Hermetic FeedthroughAssembly for Ceramic Body;” U.S. Pat. No. 7,248,912 to Gough , et al.issued Jul. 24, 2007 and entitled “Tissue implantable sensors formeasurement of blood solutes;” U.S. Pat. No. 7,871,456 to Gough et al.issued Jan. 18, 2011 and entitled “Membranes with controlledpermeability to polar and apolar molecules in solution and methods ofmaking same;” and U.S. Patent Application Publication No. 20130197332 toLucisano et al. published Aug. 1, 2013 and entitled “Tissue implantablesensor with hermetically sealed housing;” PCT Patent ApplicationPublication No. 2013016573 to Lucisano et al. published Jan. 31, 2013and entitled “Tissue implantable sensor with hermetically sealedhousing,” each of the foregoing incorporated herein by reference in itsentirety, it will be recognized by those of ordinary skill that thepresent disclosure is not so limited. In fact, the various aspects ofthe disclosure are useful with, inter alia, other types of implantablesensors and/or electronic devices.

Further, while the following embodiments describe specificimplementations of e.g., biocompatible oxygen-based multi-sensor elementdevices, and specific protocols, locations and orientations forimplantation (e.g., proximate the waistline on a human abdomen with thesensor array disposed proximate to fascial tissue; see e.g., U.S. patentapplication Ser. No. 14/982,346 filed Dec. 29, 2015 and entitled“Implantable Sensor Apparatus and Methods” previously incorporatedherein), those of ordinary skill in the related arts will readilyappreciate that such descriptions are purely illustrative, and in factcertain aspects of the methods and apparatus described herein may beused consistent with, and without limitation: (i) other implantationlocations and/or techniques; (ii) living beings other than humans; (iii)other types or configurations of sensors (e.g., peroxide-based glucosesensors, or sensors other than glucose sensors, such as e.g., for otheranalytes such as urea or lactate); and/or (iv) devices intended todeliver substances to the body (e.g. implanted drug pumps, drug-elutingsolid materials, and encapsulated cell-based implants, etc.); and/or yetother devices (e.g., non-sensors and non-substance delivery devices).

As used herein, the terms “wound healing” and “tissue response” referwithout limitation to biological processes that occur within a host orpatient during and after implantation. The biological processesgenerally including the following phases: (i) blood-biomaterialinteraction, (ii) provisional matrix formation, (iii) acuteinflammation, (iv) chronic inflammation, (v) foreign body reaction(FBR), and (vi) fibrosis/fibrous capsule development. Although eachphase is generally subsequent the preceding phase, phases maybeoverlapping and/or reoccurring.

As used herein, the term “biocompatibility” refers without limitation tothe ability of a medical device or implantable material to perform asintended in the presence of an appropriate host wound healing responseand/or other immunogenic responses, while minimizing magnitude andduration of the wound healing (e.g., acute inflammation, chronicinflammation, foreign body reaction (FBR), and fibrosis/fibrous capsuledevelopment) and causing no significant harm to the patient.

As used herein, the terms “health care provider” and “clinician” referwithout limitation to providers of health care services such as surgicalprocedures, diagnosis, monitoring, administration of pharmacologicalagents, counseling, etc., and include for instance physicians, nurses,medical assistants, technicians, and can even include the user/patientthemselves (such as where the patient self-administers, self-monitors,etc.).

As used herein, the terms “orient,” “orientation,” and “position” refer,without limitation, to any spatial disposition of a device and/or any ofits components relative to another object or being, and in no wayconnote an absolute frame of reference.

Likewise, as used herein, the terms “top,” “bottom,” “side,” “up,”“down,” and the like merely connote, without limitation, a relativeposition or geometry of one component to another, and in no way connotean absolute frame of reference or any required orientation. For example,a “top” portion of a component may actually reside below a “bottom”portion when the component is mounted to another device or object.

As used herein, the terms “detector” and “sensor” refer withoutlimitation to a device that generates, or can be made to generate, asignal indicative of a measured parameter, such as the concentration ofan analyte (e.g., glucose or oxygen). Such a device may be based onelectrochemical, electrical, optical, mechanical, thermal, or otherprinciples as generally known in the art. Such a device may consist ofone or more components, including for example, one, two, three, or fourelectrodes, and may further incorporate immobilized enzymes or otherbiological or physical components, such as membranes, to provide orenhance sensitivity or specificity for the analyte.

As used herein the term “membrane” refers without limitation to asubstance, layer or element configured to have at least one desiredproperty relative to the aforementioned analyte, such as e.g., apermeability to a given type of analyte or other sub stance.

As used herein, the terms “enzyme free” and “non-enzymatic” include,without limitation, materials that are completely enzyme-free, andmaterials that are substantially enzyme free (e.g., may have a smallpercentage of residual or unintentional enzymes).

Exemplary Implantable Sensor

Referring now to FIGS. 2-2C, one exemplary embodiment of a sensorapparatus useful with various aspects of the present disclosure is shownand described.

As shown in FIGS. 2-2C, the exemplary sensor apparatus 200 comprises asomewhat planar housing structure 202 with a sensing region 204 disposedon one side thereof (i.e., a top face 202 a). As described in greaterdetail below with respect to FIGS. 4-5, the exemplary substantiallyplanar shape of the housing 202 provides mechanical stability for thesensor apparatus 200 after implantation, thereby helping to preserve theorientation of the apparatus 200 and mitigate any tissue responseinduced by movement of the apparatus while implanted. Notwithstanding,the present disclosure contemplates sensor apparatus of shapes and/orsizes other than that of the exemplary apparatus 200.

The sensor apparatus of FIGS. 2-2C further includes a plurality ofindividual sensor elements 206 with their active surfaces disposedsubstantially within the sensing region 204 on the top face 202 a of theapparatus housing. In the exemplary embodiment (i.e., an oxygen-basedglucose sensor), the eight (8) sensing elements 206 are grouped intofour pairs, one element of each pair an active or “primary” sensor withenzyme matrix, and the other a reference or “secondary” (oxygen) sensor.Exemplary implementations of the sensing elements and their supportingcircuitry and components are described in, inter alia, U.S. Pat. No7,248,912, previously incorporated herein. It will be appreciated,however, that the type and operation of the sensor apparatus may vary;i.e., other types of sensor elements/sensor apparatus, configurations,and signal processing techniques thereof may be used consistent with thevarious aspects of the present disclosure, including, for example,signal processing techniques based on various combinations of signalsfrom individual elements in the otherwise spatially-defined sensingelements pairs.

As discussed in greater detail below with respect to FIG. 5, theillustrated embodiment of FIGS. 2-2C includes a sensing region 204 whichfacilitates some degree of “interlock” of the surrounding tissue (andany subsequent tissue response generated by the host) so as to ensuredirect and sustained contact between the sensing region 204 and theblood vessels of the surrounding tissue during the entire term ofimplantation (as well as advantageously maintaining contact between thesensing region 204 and the same tissue; i.e., without significantrelative motion between the two).

The sensor apparatus 200 also includes in the exemplary embodiment awireless radio frequency transmitter (or transceiver, depending ifsignals are intended to be received by the apparatus), not shown. Asdescribed in the aforementioned documents incorporated herein, thetransmitter/transceiver may be configured to transmit modulated radiofrequency signals to an external receiver/transceiver, such as adedicated receiver device, or alternatively a properly equipped consumerelectronic device such as a smartphone or tablet computer. Moreover, thesensor apparatus 200 may be configured to transmit signals to (whetherin conjunction with the aforementioned external receiver, or in thealternative) an at least partly implanted or in vivo receiving device,such as an implanted pump or other medication or substance deliverysystem (e.g., an insulin pump or dispensing apparatus), embedded“logging” device, or other. It is also appreciated that other forms ofwireless communication may be used for such applications, including forexample inductive (electromagnetic induction) based systems, or eventhose based on capacitance or electric fields, or even optical (e.g.,infrared) systems where a sufficiently clear path of transmission andreception exists, such as two devices in immediately adj acentdisposition.

The sensor apparatus of FIGS. 2-2C also includes a plurality (three inthis instance) of tabs or anchor apparatus 213 disposed substantiallyperipheral on the apparatus housing. These anchor apparatus provide theimplanting surgeon with the opportunity to anchor the apparatus to theanatomy of the living subject, so as to frustrate translation and/orrotation of the sensor apparatus 200 within the subject immediatelyafter implantation but before any tissue response (e.g., FBR) of thesubject has a chance to immobilize (such as via interlock with thesensing region of the apparatus. See e.g., U.S. patent application Ser.No. 14/982,346 filed Dec. 29, 2015 and entitled “Implantable SensorApparatus and Methods” previously incorporated herein, for additionaldetails and considerations regarding the aforementioned anchor apparatus213 (which may include, for example features to receive sutures(dissolvable or otherwise), tissue ingrowth structures, and/or thelike).

As shown in FIG. 3, an exemplary individual detector element 206according to the present disclosure is shown associated with detectorsubstrate 214 (e.g. ceramic substrate), and generally comprises aplurality of membranes and/or layers, including e.g., the insulatinglayer 260, and electrolyte layer 250, an enzymatic gel matrix of thetype described above 240, an inner membrane 220, an exterior membraneshell 230, and a non-enzymatic membrane 277. Such membranes and layersare associated with the structure of individual detector elements,although certain membrane layers can be disposed in a continuous fashionacross the entire detector array surface or portions thereof thatinclude multiple detectors, such as for economies of scale (e.g., whenmultiple detectors are fabricated simultaneously), or for maintainingconsistency between the individual detector elements by virtue of makingtheir constituent components as identical as possible.

Generally, the thickness of each of the membranes disclosed herein isnot particularly limited, as long as the desired permeability propertiesare achieved. However, particular requirements for sensor response time,glucose concentration detection range, and/or reduction of antibodyresponse (e.g., FBR), may impose limits on the allowable membranethickness. Membrane thickness can be, for example, about 1 micron toabout 1000 microns, or more particularly, about 10 microns to about 500microns, or more particularly about 25 microns to about 250 microns incertain applications. Very thin membrane layers, particularly those lessthan about 10 microns, may require mechanical support to be provided inthe form of a backing membrane, which may be a porous, relatively inertstructure. U.S. Pat. No. 7,336,984 and entitled “Membrane and ElectrodeStructure for Implantable Sensor,” previously incorporated herein,describes exemplary membrane apparatus, thickness values, andcomputerized modeling techniques useful with the various aspects of thepresent disclosure, although it will be recognized that othertechniques, apparatus, and methods for membrane configuration may beused consistent with the present disclosure.

As shown in FIGS. 3 and 3A, the detector elements 206 each furthercomprise a working electrode 217 in operative contact (by means of theelectrolyte layer 250) with a counter electrode 219 and a referenceelectrode 218, and their associated feedthroughs 280 (details of theexemplary feedthroughs 380 are described in U.S. Pat. No. 8,763,245 toLucisano et al. entitled “Hermetic feedthrough assembly for ceramicbody,” previously incorporated by reference herein). The workingelectrode 217 comprises an oxygen-detecting catalytic surface producinga glucose-modulated, oxygen-dependent current (discussed infra),reference electrode 218 comprises an electrochemical potential referencecontact to electrolyte layer 250, and counter electrode 219 is operablyconnected by means of electrolyte layer 250 to the working electrode 217and reference electrode 218. An electrical potentiostat circuit (notshown) is coupled to the electrodes 217, 218, and 219 to maintain afixed potential between the working and reference electrode by passingcurrent between the working and counter electrodes while preferablymaintaining the reference electrode at high impedance. Such potentiostatcircuitry is well known in the art (for an example, see U.S. Pat. No.4,703,756 to Gough et al. entitled “Complete glucose monitoring systemwith an implantable, telemetered sensor module,” incorporated herein byreference in its entirety).

The exemplary sensor apparatus of the present disclosure utilizes an“oxygen-sensing differential measurement,” by comparison of theglucose-dependent oxygen signal (i.e., from the primary orenzyme-containing sensor elements) to the background oxygen signal(i.e., from the secondary non-enzyme-containing sensor elements) thatproduces, upon further signal processing, a continuous real-time bloodglucose concentration measurement. It will be appreciated, however, thatthe methods an apparatus described herein are in no way limited to such“differential” schemes.

In one variant, the enzyme-embedded membrane includes embedded glucoseoxidase (GOx) and catalase enzymes and the sensor elements areconfigured for detection of glucose based on the following two-stepchemical reaction catalyzed by GOx and catalase as described in Armouret al. (Diabetes 39, 1519-1526 (1990)):

glucose+O₂→gluconic acid+H₂O₂

H₂O₂→½O₂+H₂O

resulting in the overall enzyme reaction (when catalase is present):

glucose+½O₂→gluconic acid

In one specific implementation, the two enzyme types (GOx and catalase,each in an excess concentration) are immobilized within a gel matrixthat is crosslinked for mechanical and chemical stability, and is inoperative contact with electrodes of each of the sensor elements, whichare configured to electrochemically sense oxygen. Glucose and ambientoxygen diffuse into the gel matrix and encounter the enzymes, the abovereactions occur, and oxygen that is not consumed in the process isdetected by the electrodes. In embodiments based on “oxygen-sensingdifferential measurement” (i.e., comparison of an active sensor readingto a reference sensor reading), after comparison of the active oxygenconcentration reading with the background oxygen concentration reading,the difference is related to glucose concentration. Thus, hydrogenperoxide produced in the initial GOx catalyzed reaction is digested tooxygen and water via the subsequent catalase catalyzed reaction, andglucose concentration may be determined via detection of oxygen.Accordingly, cell death and necrosis of the surrounding tissue due tohydrogen peroxide is mitigated, thereby at least partially mitigatingthe host wound healing response (as compared to hydrogen peroxide baseddetection sensors).

As can be seen in FIGS. 2 and 2A, the sensor pairs are radially arrangedand substantially evenly spaced apart. An active sensor and a referencesensor are adjacent pairs of sensor elements such that the arrangementwill allow each active sensor in the pair to remain within the samerelatively homogenous region of the otherwise heterogeneous tissue inwhich the device is implanted.

The electrolyte layer 250 comprises, in the illustrated embodiment, alayer of hydrophilic electrolyte material which is in direct contactwith the working electrode(s) 217, reference electrode(s) 218 andcounter electrode(s) 219. In various implementations, materials forconstructing the hydrophilic electrolyte layer 250 includesalt-containing gels comprising polyacrylamide, poly(ethylene oxide),polyhydroxyethylmethacrylate and its derivatives, and other hydrophilicpolymers and copolymers, in both crosslinked and non-crosslinked form.Various other construction details of the exemplary electrolyte layer250 are described in U.S. Patent Application Publication No.2013/0197332 filed Jul. 26, 2012 entitled “Tissue Implantable SensorWith Hermetically Sealed Housing,” incorporated by reference herein inits entirety.

In an exemplary embodiment, the enzymatic material 240 comprises acrosslinked gel of hydrophilic material including enzymes (e.g., glucoseoxidase and catalase) immobilized within the gel matrix, including abuffer agent and small quantities of a chemical crosslinking agent. Thehydrophilic material 240 is permeable to both a large molecule component(e.g. glucose) and a small molecule component (e.g. oxygen). In variousembodiments, specific materials useful for preparing the enzymaticmaterial 240, include, in addition to an enzyme component,polyacrylamide gels, glutaraldehyde-crosslinked collagen or albumin,polyhydroxy ethylmethacrylate and its derivatives, and other hydrophilicpolymers and copolymers, in combination with the desired enzyme orenzymes. The enzymatic material 240 can similarly be constructed bycrosslinking glucose oxidase or other enzymes with chemical crosslinkingreagents, without incorporating additional polymers.

The enzymatic material 240 is in operative contact with the workingelectrode 217 through the inner membrane 220 and the electrolyte layer250 to allow for the electrochemical detection of oxygen at the workingelectrode 217 modulated by the two-step chemical reaction catalyzed byglucose oxidase and catalase discussed above. To that end, as glucoseand ambient oxygen diffuse into the enzymatic material 240 from theouter (non-enzymatic) membrane 277, they encounter the resident enzymes(glucose oxidase and catalase) and react therewith; the oxygen that isnot consumed in the reaction(s) diffuses through the inner membrane 220and is detected at the working electrode 217 to yield aglucose-dependent oxygen signal. Advantageously, as discussed in greaterdetail below, any transiently created peroxide is scavenged by thecatalase, which further enhances the non-immunogenic properties of thesensor as a whole.

A hydrophobic material is utilized for inner membrane 220, which isshown in FIG. 3 as being disposed over the electrolyte layer 250. Thehydrophobic material is impermeable to the larger or less solublemolecule component (e.g. glucose) but permeable to the smaller or moresoluble molecule component (e.g. oxygen). In various embodiments,materials useful for preparing hydrophobic layers, including innermembrane 220, as well as membrane shell 230, include organosiliconpolymers, such as polydimethylsiloxane (PDMS) and derivatives thereof,polymers of tetrafluoroethylene, ethylene tetrafluoroethylene, orfluorochloro analogs alone or as copolymers with ethylene or propylene,polyethylene, polypropylene, cellulose acetate, and otheroxygen-permeable polymeric materials.

The inner membrane 220 can also be a continuous layer across the entiredetector array surface, and thus be a single common layer utilized byall detectors in the detector array (assuming a multi-detector array isutilized). It is noted that the inner membrane 220, inter alia, protectsthe working electrode 217, reference electrode 218 and counter electrode219 from drift in sensitivity due to contact with certain confoundingphenomena (e.g. electrode “poisoning”), but the working electrode 217will nonetheless be arranged sufficiently close to the enzymaticmaterial to enable detection of oxygen levels therein.

The (hydrophobic) outer membrane shell 230 is disposed over at least aportion of the enzymatic material 240 (forming a cavity 271 within whichthe material 240 is contained), and is further configured to include anaperture within a “spout” region 270. It is contemplated that the innermembrane 220 and the membrane shell 230 can be coextensive and thereforebe disposed as one continuous membrane layer in which outer membraneshell 230 and inner membrane 220 are of the same uniform thickness ofmembrane across the individual detector and array, although it will beappreciated that other thicknesses and configurations may be used aswell, including configurations wherein the membrane shell 230 isseparately provided and adhesively bonded to the inner membrane 220.

However, as shown in FIG. 3, inner membrane 220 and membrane shell 230are disposed in a manner that creates discrete three-dimensional regionshaving different thicknesses on the detector substrate 214, which can beutilized to create tissue anti-migration elements used to achievestability of location, prevention of device migration away from itsoriginal implant location, and prevention of local tissue slippage inthe vicinity of the detector element 206. Alternatively, the hydrophobiccomponent may be dispersed as small domains in a continuous phase of thehydrophilic material. Various other construction details of thehydrophobic component dispersed as small domains in a continuous phaseof hydrophilic material are described in U.S. Pat. Nos. 4,484,987 and4,890,620, each incorporated herein by reference in its entirety.

As shown in FIGS. 3-3A, the single spout region 270 of the (primary)detector element 206 forms a small opening or aperture 276 through themembrane shell 230 to constrain the available surface area ofhydrophilic enzymatic material 340 exposed for diffusionally acceptingthe solute of interest (e.g. glucose) from solution. Alternatively, itis contemplated that on or more spout regions (and or apertures within aspout region) can exist per detector element.

The shape and dimension of spout region 270 aids in controlling the rateof entry of the solute of interest (e.g. glucose) into enzymaticmaterial 240, and thus impacts the effective operational permeabilityratio of the enzymatic material 240. Such permeability ratio can beexpressed as the maximum detectable ratio of glucose to oxygenconcentration of an enzymatic glucose sensor, where such a sensor isbased on the detection of oxygen unconsumed by the enzyme reaction, andafter taking into account the effects of external mass transferconditions and the enzyme reaction stoichiometry. Detailed discussionsof the relationship between membrane permeability ratio and the maximumdetectable ratio of glucose to oxygen concentration of oxygen-detecting,enzymatic, membrane-based sensors are provided in “Model of aTwo-Substrate Enzyme Electrode for Glucose,” J. K. Leypoldt and D. A.Gough, Analytical Chemistry, 56, 2896 (1984) and “Diffusion and theLimiting Substrate in Two-Substrate Immobilized Enzyme Systems,” J. K.Leypoldt and D. A. Gough, Biotechnology and Bioengineering, XXIV, 2705(1982), incorporated herein by reference. The membranes of the exemplarydetector element described herein are characterized by a permeabilityratio of oxygen to glucose of about 200 to about 1 in units of (mg/dlglucose) per (mmHg oxygen). Note that while this measure of permeabilityratio utilizes units of a glucose concentration to an oxygenconcentration, it is nevertheless a measure of the ratio of oxygen toglucose permeability of the membrane.

The exemplary spout 270 is formed out of the hydrophobic material of themembrane shell 230 without bonded enzymes (e.g., silicone rubber) andadvantageously includes a non-enzymatic outer layer or membrane 277 to,inter alia, prevent direct contact of the immobilized enzymes in theenzymatic material 240 with the surrounding tissue, thereby mitigatingtissue response (e.g., FBR), encapsulation, and/or other deleteriousfactors. In the exemplary embodiment, the non-enzymatic membrane 277 isfurther constructed (i.e., with a substantially planar, crosslinkedbiocompatible matrix possessing pores substantially smaller than thoserequired to accommodate blood vessel ingrowth, but large enough toaccommodate diffusion of solutes of interest) so as to frustrate ormitigate blood vessel formation therein.

Herein lies a salient feature of the sensor element of the exemplaryembodiment; i.e., the combination of (i) an enzyme-free biocompatibleouter membrane 277, (ii) maintenance of the spout region substantiallyfree of enzyme material during manufacture, (iii) use of a low-porediameter, crosslinked structure for the membrane 277, and (iv) use of abiocompatible material (e.g., silicone rubber) for the outer membraneshell 230, dramatically reduce the level of tissue response of the hostwhile the device is implanted, thereby allowing for both longerimplantation (due to, inter alia, the reduced level of tissue responsenot interfering with sensor operation) and easier explants of thedevice, as compared to e.g., peroxide-based sensors without one or moreof such features. In one exemplary embodiment, the outer (non-enzymatic)membrane 277 has an average pore diameter on the order of five (5) toten (10) microns, with the individual pore diameters distributednormally (i.e., according to a substantially Gaussian distributionfunction). See, e.g., Xiaoyu Ma, et al—“A Biocompatible andBiodegradable Protein Hydrogel with Green and Red Autofluorescence:Preparation, Characterization and In Vivo Biodegradation Tracking andModeling,” Scientific Reports (Nature.com) published Jan. 27, 2016,incorporated herein by reference in its entirety, for discussion ofexemplary albumin-based substances and pore-size related features andconsiderations.

In another embodiment, the outer membrane has a maximum pore diametervalue of less than 5 microns (i.e., on the order of 3 microns), suchthat the population of individual pores are substantially all below orequal to such value. In yet another implementation, a median porediameter (which may be different than the aforementioned mean) is usedas a basis for characterization of the outer membrane 277.

The inner hydrophobic membrane 220 further provides additionalinsulation of the host tissue in the region of the detector 206 againstany electrical potentials or currents which may be present within thesensor element, thereby further aiding in mitigating any undesiredtissue response. Further, use of a solid polymer layer 220 (e.g., formedof PDMS) disposed between the inner enzyme embedded membrane and sensingelements (i.e., electrodes) further assists in preventing passage ofcurrent from the electrodes into the surrounding tissues, and limitingpossible exacerbation of tissue encapsulation (e.g., FBR, fibrosis,etc.) due to electrical flux, which may be problematic for some otherconventional implanted sensors. Furthermore, the housing may behermetically sealed to prevent exposure of tissue to electrical currentsand/or internal components of the sensor.

In one example, an outer membrane 277 of a crosslinked albumin may beutilized. Additionally, other biostable polymers suitable as coatingmembranes include biocompatible materials, such as e.g., hydrophilicpolyurethanes, silicones, poly(hydroxyethylmethacrylate)s, polyesters,polyalkyl oxides (polyethylene oxide), polyvinyl alcohols, polyethyleneglycols, and polyvinyl pyrrolidone. Other polymers may also be usedprovided they can be dissolved, cured, or otherwise fixed or polymerizedon the sensor housing. These may include polyolefins, polyisobutyleneand ethylene-alphaolefin copolymers; acrylic polymers (includingmethacrylates) and copolymers, vinyl halide polymers and copolymers,such as polyvinyl chloride; polyvinyl ethers, such as e.g., polyvinylmethyl ether; polyvinylidene halides, such as e.g., polyvinylidenefluoride and polyvinylidene chloride; polyacrylonitrile, polyvinylketones; polyvinyl aromatics, such as e.g., polystyrene; polyvinylesters, such as e.g., polyvinyl acetate; copolymers of vinyl monomerswith each other and olefins, such as e.g., ethylene-methyl methacrylatecopolymers, acrylonitrile-styrene copolymers, ABS resins andethylene-vinyl acetate copolymers; polyamides, such as e.g., Nylon 66and polycaprolactam; alkyd resins; polycarbonates; polyoxymethylenes;polyimides; polyethers; epoxy resins, polyurethanes; rayon;rayon-triacetate, cellulose, cellulose acetate, cellulose acetatebutyrate; cellophane; cellulose nitrate; cellulose propionate; celluloseethers, such as e.g., carboxymethyl cellulose and hydroxyalkylcelluloses; and combinations thereof. Polyamides for the purpose of thisapplication would also include polyamides of the form —NH—(CH₂)_(n)—CO—and NH—(CH₂)_(x)—NH—CO—(CH₂)_(y)—CO, wherein n is preferably an integerin from 6 to 13, x is an integer in the range of form 6 to 12, and y isan integer in the range of from 4 to 16.

It will be appreciated that the relatively smaller dimensions of thesensor apparatus (as compared to many conventional implantdimensions)—on the order of 40 mm in length (dimension “a” on FIGS.2A-2C) by 25 mm in width (dimension “b” on FIGS. 2A-2C) by 10 mm inheight (dimension “c” on FIGS. 2A-2C)—may reduce the extent of injury(e.g., reduced size of incision, reduced tissue disturbance/removal,etc.) and/or the surface area available for blood/tissue and sensormaterial interaction, which may in turn reduce intensity and duration ofthe host wound healing response. It is also envisaged that as circuitintegration is increased, and component sizes (e.g., lithium or otherbatteries) decrease, and further improvements are made, the sensor mayincreasingly be appreciably miniaturized, thereby further leveragingthis factor.

It is also appreciated that some flexibility in component locationexists; as such, the present disclosure further contemplates e.g.,relocation of certain components within the implanted sensor device 200such as those associated with signal processing, off-device (i.e., in anexternal receiver module or other electronic apparatus external to theimplanted sensor, such as a user's smartphone or tablet computer, orother implanted or external medical device) so as to further minimizeinterior sensor device volume/area requirements. For instance, in onesuch adaptation, electronic components such as antennas and/or circuitboards (e.g., PCBs) can be wholly or partly replaced with so-called“printable” electronics which reside on, e.g., interior components orsurfaces of the sensor device 200, such as by using the methods andapparatus described in U.S. Pat. No. 9,325,060 issued Apr. 26, 2016 andentitled “Methods and apparatus for conductive element deposition andformation,” which is incorporated herein by reference in its entirety.Other types of space/area-reducing adaptations will be readilyrecognized by those of ordinary skill in the electronic arts when giventhe present disclosure. Returning again to FIGS. 2-2C, the housing 202and sensing region 204 purposely have relatively smooth outer surfaces,which may be comprised of biocompatible materials, thereby limitingreaction of the tissue to the sensor apparatus 200 and allowinglong-term implantation. Specifically, by providing a smooth surface overmuch of the sensor housing and forming the housing (and other externallyexposed components) of materials which do not incite tissue response(e.g., titanium), very little if any bonding or attachment of the tissueresponse to the sensor housing or other such components occurs, evenafter an extended period of implantation (i.e., 12 months or more).Biocompatible materials may be used at least where any portion of thesensor comes into physical contact with the body. Exemplarybiocompatible materials are disclosed in U.S. Patent Publication No.20130197332, previously incorporated herein. A variety of suitablemedical grade materials are known in the art which may be utilized toconstruct the housing; e.g., a metallic material or an alloy such as,but not limited to, bio-inert metals, cobalt-chromium alloys, alloys ofcobalt, nickel, chromium and molybdenum, stainless steel, tantalum,tantalum-based alloys, nickel-titanium alloy, platinum, platinum-basedalloys such as e.g., platinum-iridium alloy, iridium, gold, magnesium,titanium, titanium-based alloys, zirconium-based alloys, or combinationsthereof. Further, the housing may be constructed from biocompatibleceramic materials, comprising oxides, carbides, borides, nitrides, andsilicides of aluminum, zirconium, beryllium, silicon, titanium, yttrium,hafnium, magnesium and zinc.

Furthermore, the housing may also be made from biocompatible, biostablepolymers, such as polymers including but not limited to fluorpolymers(e.g., DuPont Teflon® or Tefzel® or the like), epoxy resins,polyetherimides, poly ether ketone, polysulfone, polyphenylsulfone,polypropylene, polycarbonate, poly methyl methacrylate, and others,which may present a smooth and substantially non-adherent surface incertain formulations.

Notably, however, the sensing region 204 of the exemplary sensorapparatus 200 purposely includes some level of texture or relief (albeitwith biocompatible materials as well), so as to give any tissue responseor encapsulation in that region something to “grab onto” to promote theclose contact, interlock, and anti-slip described herein with respect toFIG. 5. Such texture or relief can be provided in one or more ways,including e.g., via a roughened or “bumpy” material texture, and/or oneor more prominent or salient features elevated and/or depressedover/within the surrounding portions of the apparatus (i.e.,irrespective of texture of the materials). As previously referenced,this arrangement also helps maintain the sensor element active areas(i.e., the outer non-enzymatic membrane 277 and its underlying enzyme inthe “primary” sensor elements, and the membrane 277 with non-enymaticmatrix in the “secondary” sensor elements) maintain a substantiallyconstant, direct, and non-variable level of contact with particularblood vessels located in the tissue of that region, so as to maximizethe stability and accuracy of the signals generated from each of thesensor elements. Specifically, the absence of relative motion betweeneach individual sensor primary or secondary element and the surroundingtissue and vasculature allows the sensor to receive a substantiallyconstant blood (and hence glucose) supply over time, which translates toa substantially constant rate of glucose diffusion through the outermembrane 277 and into the underlying matrix.

Implantation to Minimize Tissue Response and Maximize Detector Contact

Previously incorporated U.S. patent application Ser. No. 14/982,346filed Dec. 29, 2015 and entitled “Implantable Sensor Apparatus andMethods” describes exemplary “deep” implantation techniques useful withthe apparatus and methods of the present disclosure; specifically, inthe exemplary embodiment of such techniques, the sensor apparatus 200 isimplanted surgically near the abdominal muscle fascia and in contactwith the solid tissue within a pocket formed in the host's lowerabdomen; see FIG. 4 herein. Specifically, once the cavity or pocket 401is formed, the sensor apparatus 200 is implanted within thecavity/pocket in the direction 400 shown, so that the sensing region 204is both proximate the target fascial layer (and contacting the localsolid tissue) and oriented in the desired direction. In one variant, theuser's superficial (scarpal) fascia is incised, and the adipose tissue405 immediately proximate the deeper fascial membrane 402 (i.e.,anterior abdominal fascia; see FIG. 4) is merely separated from thefascial membrane so as to form the desired cavity or pocket 401, withlittle or no tissue removal from the patient. Such separation ispreferably performed using “blunt” techniques (i.e., without cutting perse), to minimize tissue and blood vessel trauma, and also mitigateprospective FBR (which may be exacerbated from cutting versus bluntformation), but may also be performed using an instrument such as ascalpel or surgical scissors if needed or desired for other reasons.

As described supra, in addition to potentially creating inconsistenciesor variations in interaction between each sensor element and itssurrounding vasculature (and hence reducing inter alia, device accuracyover time), undesired movement of the implanted sensor apparatus mayalso contribute to increased chronic inflammation (which can have itsown set of deleterious effects). Therefore, limiting undesired movementmay also advantageously mitigate the host's tissue response to theimplanted sensor. The somewhat planar shape of the sensor housing 202helps to maintain the desired sensor orientation and placement;accordingly, the sensor apparatus 200 is inserted into the cavity 401with the “flat” sides substantially parallel to the plane of the fasciallayer 402, musculature 404, superficial fascia 406, superficial fattytissue layer 407, and epidermis 408. In one variant, the sensorapparatus 200 is oriented “round side up”, such that the rounded end 211(see FIG. 2) is inserted into the formed pocket first, thereby aiding inplacement with minimal friction and effort.

The mechanical stability provided by the substantially planar shape ofthe housing 202 after implantation helps to preserve the orientation ofthe apparatus 200 (e.g., with sensing region 204 facing away from theepidermis and toward the proximate fascial layer), resisting rotationaround its longitudinal axis 208, and translation, or rotation about itstransverse axis 210, which might otherwise be caused by e.g., normalpatient ambulation or motion, sudden accelerations or decelerations (dueto e.g., automobile accidents, operation of high-performance vehiclessuch as aircraft), or other events or conditions.

Notwithstanding, the present disclosure contemplates sensor apparatus ofshapes and/or sizes other than that of the exemplary apparatus 200,including use of means for maintaining the desired orientation andposition such as e.g., the plurality of tabs or anchor apparatus 213disposed substantially peripheral on the apparatus housing (FIGS.2A-2C), which provide the implanting surgeon with the opportunity toanchor the apparatus to the anatomy of the living subject, so as tofurther frustrate translation and/or rotation of the sensor apparatus200 within the subject immediately after implantation but before anytissue response of the host has a chance to immobilize the device, suchas via interlock with the sensing region of the apparatus discussedbelow with respect to FIG. 5).

The sensor apparatus may additionally or alternatively include one ormore anti-migration features described in U.S. Pat. No. 7,871,456, andU.S. Patent Publication No. 20130197332, each of which is previouslyincorporated herein. In one variant, an outer surface of the housing mayinclude one or more anti-migration elements, which promote adherence ofthe sensor apparatus to the surrounding tissue. In some embodiments, abiocompatible mesh, fabric or three-dimensional structure comprised ofe.g., polymeric, metallic, and/or ceramic materials may be disposed on asurface of the housing for encouraging ingrowth of tissues (e.g., viatissue regeneration and/or fibrosis) into such anchor or anti-migrationelements. In other embodiments, tissue anti-migration elements may alsoinclude coatings or agents for enhancing or promoting cellularattachment as well as ingrowth, such as cell adhesion molecules, e.g.,fibronectin and laminin, as well as anti-thrombotic and/or anti-plateletagents, such as e.g., heparin. As noted above, undesired movement(translation, rotation) of the sensor apparatus is further inhibitedafter implantation through physiological interaction (e.g., tissueregeneration, FBR, fibrosis, etc.) of the sensor apparatus with the hostsubject at the site of implantation. For example, clinical trials of theexemplary apparatus 200 by the Assignee hereof indicate that some degreeof tissue “contouring” or “imprinting” with at least the sensing region204 (e.g., a raised sensing region) occurs over the duration of atypical implantation, due to inter alia normal biological processeswithin the host, as shown in the depiction of FIG. 5. In effect, thehost's tissue 405 closely contacts and develops contours directlyreflective of the shape of the sensing region 204 (and specifically theouter membrane element 230 and non-enzymatic membrane 277), therebyindirectly providing enhanced mechanical coupling, and attendantresistance to movement. Vascularization (i.e., the in-growth ofmicro-sized blood vessels) into the sensor element outer membrane 230and non-enzymatic membrane 277 is also advantageously and purposelyfrustrated as previously noted, thereby making the implanted sensorapparatus readily separated from the surrounding solid tissue 405 atexplant, even after extended periods of time, since few if any suchblood vessels need be severed to effect physical separation of thedevice from the tissue in the sensing region 204, as well as otherportions of the device housing as previously described. Hence, theexemplary apparatus and techniques of the present disclosure cooperateto enable a small but deep implantation of the device 200 whichadvantageously immobilizes it, maintains constant and predictable bloodvessel and sensor contact, yet engenders very little tissue response andencapsulation, and little if any vascularization, thereby bothmitigating effects of such confounding tissue response on the detectorelements 206, and making for easy subsequent explants.

It is appreciated that some degree of separation or “gaps” 488 may existbetween the host tissue and the sensor element outer components (asshown in FIG. 5) due to e.g., recesses or artifacts present in the shapeof the outer sensor components, or for biological reasons; however, solong as substantially intimate contact is maintained over a majority ofthe surface areas of the detector sensing region 204, the correlation ofthe detector output with analyte concentration within the blood vesselsof the neighboring tissue remains stable, helping to ensure sensoroverall sensor accuracy and utility.

As described supra, it is also envisaged that as circuit integration isincreased, and component sizes (e.g., lithium or other batteries)decrease, and further improvements are made, the sensor may increasinglybe appreciably miniaturized, and further that successively smaller andsmaller incisions are required for implantation of the sensor apparatusover time. Laparoscopic implantation, or even a coarse “injection”delivery by trocar are also feasible methods of implantation withappropriate adaptation, such adaptation being well within the skill ofan ordinary artisan in the medical or surgical arts when given thepresent disclosure. It will be appreciated that the smaller dimensionsof the sensor apparatus may reduce the extent of injury (e.g., eliminateneed for an incision during implantation, reduced size of incision,reduced tissue removal, etc.), which in turn may reduce intensity and/orduration of the host wound healing response, thereby even furtherleveraging the advantageous aspects of the methods and apparatusdisclosed above.

In one variant, the detectors of the sensor apparatus 200 are alsoadvantageously insensitive to interfering or confounding substances;e.g., low molecular weight species such as acetaminophen (e.g.,Tylenol®-C₈H₉NO₂; molecular weight 151.16). As is known, while theglucose oxidase enzyme is highly specific to the glucose molecule,migration of acetaminophen through to the sensing electrodes canadversely impact operation of a peroxide-based implantable glucosesensor, such adverse impact being severe enough to warrantcontra-indication of acetaminophen for the host during monitoring.Contra-indication of such a common pain reliever is highly undesirablefrom a practical standpoint; the host must strictly utilize an alternateover-the-counter pain reliever which is not contra-indicated. Moreover,one errant ingestion by the host during monitoring (e.g., mistakenlyswallowing acetaminophen versus a non-contra-indicated substance) cancause significant errors in the estimated blood glucose level, often ina non-conservative direction which can even be life-threatening to thehost (i.e., erroneously indicating that the subject has a greater bloodglucose level than they actually do, and either causing the host totreat the erroneously-elevated glucose level with glucose-loweringmedication or avoid taking action which could otherwise mitigate anactual low blood glucose condition).

Such issues are avoided by the exemplary sensor configuration through,inter alia, use of an oxygen-based electrode apparatus which iseffectively insensitive to oxidizing agents such as acetaminophen.Specifically, the exemplary sensor apparatus 200 couples thehighly-specific enzyme glucose oxidase to electrodes sensitive tooxygen, eliminating the influence from non-glucose substances. Utilizingan oxygen-sensitive electrode also allows the co-localization ofcatalase, a high affinity enzyme that converts the hydrogen peroxideproduced by the glucose oxidase to water and oxygen. This preventsrelease of the hydrogen peroxide into the surrounding tissues,minimizing inflammation and the foreign body response, while having anadditive benefit of regenerating half of the oxygen consumed by glucoseoxidase. Notwithstanding, the inner membrane of the sensor apparatus 200may be configured to block or interfere with the permeation ofundesirable species such as acetaminophen. In one variant, such blockageof undesired species is accomplished through use of an inner membranehaving a prescribed pore size; i.e., large enough to permit themigration of oxygen molecules to the electrodes, yet small enough toblock undesired species such as acetaminophen. See, e.g., U.S. Pat. No.5,804,048 entitled “Electrode assembly of assaying glucose”,incorporated herein by reference in its entirety, which describes oneexemplary approach to utilizing a membrane within a glucose sensor toblock undesirable molecular species from reaching sensing electrodes,although it is appreciated that other approaches may readily be usedconsistent with the present disclosure.

Anecdotal Performance

Human clinical trials conducted by the Assignee hereof authorized by theU.S. Food and Drug Administration (FDA) to date indicate superiorperformance of the foregoing techniques and apparatus, including notably(i) the ability of the sensor apparatus to remain implanted for extendedperiods without deleterious foreign body response to the sensor from thehost which impairs the operation of the sensor, (ii) generalinsensitivity to ingested or locally injected substances which mightotherwise interfere with the performance of the device (e.g.,acetaminophen, insulin injections, etc.) and (iii) the ability of thesensor apparatus to provide a stable output for extended (e.g., multipleweek) intervals. These advantages are due at least in part by virtue ofthe selected target location being deep(er) within the abdominalsubcutaneous tissue of the patient (e.g., proximate the fascia), and theorientation of the sensing region of the apparatus 200 away frompossible sources of interference or degradation, as well as constructiondetails described above (e.g., use of a non-enzymatic outer membrane,maintenance of the aperture of the sensor outer membrane or housingenzyme-free, insulation of electrical currents or potentials, use ofbiocompatible materials, use of sensing region shape and constructionwhich promotes close contact and interlock with the surrounding tissue,and minimization of the size of the implanted device).

FIG. 6 herein is a plot of “proximity index” vs. average sensor O₂ levelat 12 weeks (implanted duration), which illustrates exemplary anecdotaldata obtained by the Assignee hereof during trials of a generallycomparable sensing device and using, inter alia, ultrasound techniques.Specifically, the data of FIG. 6 demonstrates the aforementionedstability of output for extended periods, which is in part afforded bythe sensor device's access to the blood supply by virtue of its “deep”placement and mitigation of tissue response as noted above.

Each point on the graph of FIG. 6 represents the average of the outputfrom the four (4) oxygen reference or “secondary” electrodes on a givenimplanted device. The “proximity index” metric of FIG. 6 provides anindication of the distance between the sensing area aspect of theimplanted device and the underlying muscle layer. Any positive value ofthe index indicates physical separation (i.e., lack of intimate contactbetween the sensing area and the target tissue such as the musclefascia). Conversely, any negative index value indicates close contactbetween the sensing area and the muscle fascia. Hence, as can be seen inFIG. 6, where close physical contact of the sensing area of the deviceand the muscle fascia was maintained, including the aforementioned“interlock” of the tissue with the sensing area, sensor output wasnotably elevated compared to cases where close contact between thesensing area of the device and the muscle fascia was not achieved.

Imprint Re-Use Methods

Referring now to FIG. 7, methods of surgical implantation leveraging thetissue “imprint” previously described herein are discussed in detail.Specifically, as noted supra, the foregoing imprint created by thesensor apparatus 200 upon continued implantation within a host for aperiod of time can be advantageously re-used, whether by (i) asubsequent replacement sensor of the same or similar configuration asthat originally implanted, or (i) the same sensor apparatus that hasbeen e.g., explanted, refitted with a new battery or other component(s),or otherwise made suitable for re-implantation, so that the foreign bodyresponse or other deleterious host responses are yet further avoided,and trauma to the host is minimized. As noted, the construction of theexemplary sensor apparatus 200 includes biocompatible materials andother features (including albumin outer membrane in someimplementations) which enable the surrounding host tissue to come inclose physical contact with the sensor apparatus (and especially thesensing region thereof), yet avoid any significant bonding or attachmentthereto. Hence, explant of the sensor apparatus (even after significantperiods of time, such as 12 months or more) is readily conducted, witheffectively no trauma to the contacting tissue (i.e., the sensorapparatus more or less “peels away” from the tissue without significantdamage or alteration thereto, since there is effectively no bonding orblood vessel vascularization into or onto the sensor apparatus).

Hence, after explant, the imprint on the tissue remains essentiallyintact, and can be utilized by the subsequently implanted sensorapparatus (assuming similar configuration in at least the sensingregion). This approach yet further mitigates body response that mightoccur from the explant and subsequent implant. Moreover, when using the“deep” surgical implantation techniques previously described andincorporated by reference herein, and a substantially identicalreplacement sensor configuration, the same surgical incision, pocket,and sensor orientation can be utilized—the host in effect sees thereplacement apparatus as an exact fit for the explanted device (samesize, same materials, etc.), and hence no further body response isgenerated. This process of explant and replacement with a similarapparatus in the same pocket and imprint can be performed almostindefinitely, since (i) the duration of implantation is long (e.g., 12months or more) and hence the (reused) incision has plenty of time toheal; and (ii) the lack of any subsequent significant body responseavoids any other processes within the body which might otherwise limitreuse of the same implantation location on the host.

Moreover, by using the same imprint within the tissue, the replacementsensor apparatus is immediately “locked into” position (contrast theoriginal implantation, wherein a period of time is required for the hosttissue to imprint or form closely around all of the features of thesensor apparatus as in FIG. 5), and hence any body response due to e.g.,relative movement between the sensor apparatus 200 and surroundingtissue, is substantially avoided. It is envisioned that in certaincases, such immediate position lock on the second and subsequentimplants can even be used as a basis for selectively obviating use ofdissolvable sutures or other anchoring mechanisms described herein,since the imprint (and other contours developed around the prior sensorapparatus in the pocket) effectively perform the same function.Obviating trauma (however mild) due to e.g., suturing may yet furthermitigate formation of any undesired body response.

As shown in FIG. 7, the exemplary embodiment of the method 700 firstincludes implantation of the “first” sensor apparatus (original, orotherwise) into the host using, e.g., the implantation techniquespreviously described, per step 702.

Next, the implanted sensor apparatus is operated in vivo; e.g., until ithas reached its design implantation duration, its battery is showingsigns of expiration, (e.g., via voltage readings across its terminals,etc.), or based on yet other criteria, ideally using the same incisionas used for implantation (step 704).

The implanted sensor is then explanted (step 706), and a “second” sensorapparatus (which may be the same as originally implanted, or another ofsimilar design/configuration as described above) is implanted, andoriented as identically as possible to the orientation of the firstsensor apparatus (step 708). During implantation, the implanted (second)apparatus is secured if/as needed, such as via dissolvable suture (step710). The second sensor is then operated for its prescribed period(e.g., operational lifetime) per step 712, and then subsequentlyexplanted and replaced as needed per step 714, i.e., similar to steps706 through 712.

Adaptation Circuitry and Methods

In some cases of implantation, the FBR and/or fibrosis phases of woundhealing may block or cover one or more of the sensor elements 206. Thesensor apparatus, however, includes multiple (4) sets of sensing andreference sensing elements, which are in one implementation adapted todynamically compensate for e.g., FBR, fibrosis, or other so-called“confounding factors” (described in U.S. Pat. No. 7,248,912, previouslyincorporated herein) occurring proximate the sensing elements, therebymaintaining the accuracy of the device as a whole. Specifically, thesensor apparatus 200 may have the advantage that the active sensorreading is compared to the reference sensor for glucose detection (i.e.,“oxygen-sensing differential measurement”, described supra). Thus, ifthe active sensor is blocked by foreign body giant cells, granulationtissues, and/or fibrous host tissue, it is likely that the adjacentreference sensor is also blocked. Readings from the sensing element pairwill indicate that they are non-functional and should be excluded fromdetermining the diabetic patient's glucose level.

The sensor apparatus 200 has the further advantage that if one or morepairs of sensors are non-functional, the glucose level may be determinedfrom the remaining sensor pairs. Accordingly, as sensing elements orsets thereof become inoperative or unreliable, these elements/sets canbe selectively removed from the signal processing logic and deactivatedwhile other sensor pairs remain active. Alternatively, the weight of anysignals generated by such compromised elements or pairs may be reducedover time so as to progressively reduce their contribution to the“composite” signal generated by the device.

Moreover, the aforementioned ability to remove or reduce thecontribution of a given detector element or pair enables compensationfor detector failure due to, e.g., leakage or other fault. As notedelsewhere herein, the exemplary sensor apparatus maintains the regionsof each detector contacting the host's solid tissue enzyme-free (boththrough use of the non-enzymatic membrane 277 of FIG. 3 andmanufacturing processes which avoid contamination of the spout region370 with the enzyme matrix of the cavity), and electrically insulated.However, in the case of a manufacturing defect, failure of a component(e.g., non-enzyme membrane 277 or outer membrane 230), or other suchoccurrence, the tissue response in a region localized to that (failed)detector element may increase due to the presence of the enzyme,electrical stimulation, etc., which can result in degradation of theperformance of that particular detector element (if not already degradeddue to component failure). By identifying such failures or tissueresponses, the affected detector(s) can be electrically removed fromfurther signal processing while the sensor 200 is implanted.

Exemplary apparatus and methods for evaluating and adjusting operationof an implanted analyte (e.g., glucose) sensor which may be usedconsistent with the present disclosure are described in U.S. Pat. No.7,248,912 to Gough , et al. issued Jul. 24, 2007 and entitled “Tissueimplantable sensors for measurement of blood solutes”, previouslyincorporated herein, although it will be appreciated that otherapparatus and methods may be used alternatively or in addition to thosedescribed in U.S. Pat. No. 7,248,912.

It will be recognized that while certain embodiments of the presentdisclosure are described in terms of a specific sequence of steps of amethod, these descriptions are only illustrative of the broader methodsdescribed herein, and may be modified as required by the particularapplication. Certain steps may be rendered unnecessary or optional undercertain circumstances. Additionally, certain steps or functionality maybe added to the disclosed embodiments, or the order of performance oftwo or more steps permuted. All such variations are considered to beencompassed within the disclosure and claimed herein.

While the above detailed description has shown, described, and pointedout novel features as applied to various embodiments, it will beunderstood that various omissions, substitutions, and changes in theform and details of the device or process illustrated may be made bythose skilled in the art without departing from principles describedherein. The foregoing description is of the best mode presentlycontemplated. This description is in no way meant to be limiting, butrather should be taken as illustrative of the general principlesdescribed herein. The scope of the disclosure should be determined withreference to the claims.

1.-37. (canceled)
 38. An implantable analyte sensor, comprising: abiocompatible housing having a size and shape suitable for implantationin a body; a plurality of analyte detectors; and circuitry operativelyconnected to the plurality of detectors and configured to: process atleast a portion of signals generated by one or more of the detectors toproduce processed signals, and generate a composite signal using theprocessed signals; at least one data transmission apparatus configuredto transmit the composite signal to a receiver when the implanted sensoris disposed in a tissue environment within said body; and an electricalpower source operatively coupled to at least the circuitry and datatransmission apparatus and configured to provide electrical powerthereto; wherein the sensor further comprises apparatus configured topromote adaptation of biological tissue of the body proximate to atleast a portion of said plurality of detectors without substantive bloodvessel ingrowth.
 39. The sensor of claim 38, wherein the analytecomprises blood glucose, and the apparatus configured to promoteadaptation comprises at least one membrane configured for direct contactwith the biological tissue after implantation of the implantable analytesensor, the at least one membrane at least partly permeable to diffusionof the blood glucose therethrough, yet which is configured to frustrateblood vessel ingrowth.
 40. The sensor of claim 39, wherein theconfiguration to frustrate blood vessel ingrowth comprises formation ofthe at least one membrane with a prescribed pore size at least on anouter surface thereof, the prescribed pore size selected to limit theblood vessel ingrowth yet permit said diffusion of said blood glucosetherethrough.
 41. The sensor of claim 39, wherein the at least onemembrane is formed using a substantially liquid or flowable substanceand subsequent curing thereof using a chemical crosslinking agent. 42.The sensor of claim 39, wherein the plurality of analyte detectors eachcomprise an enzymatic material, and said at least one membrane comprisesa plurality of respective membranes configured to isolate said tissuefrom respective ones of said enzymatic material of each analyte detectorat least while said sensor is implanted in said body.
 43. The sensor ofclaim 42, wherein: the enzymatic material comprises a glucose oxidaseand a catalase, and configured to at least transiently produce hydrogenperoxide based at least on a reaction of said blood glucose and saidglucose oxidase; and said plurality of membranes are each configured toprovide a physical separation between the enzymatic material and thetissue adjacent to the sensor.
 44. The sensor of claim 43, wherein eachof said plurality of membranes comprise a chemically crosslinkedalbumin-based material.
 45. The sensor of claim 43, wherein: theenzymatic material comprises a glucose oxidase and a catalase, andconfigured to at least transiently produce hydrogen peroxide as part ofa reaction of said blood glucose and said glucose oxidase; said analytedetectors each comprise an outer body element having an aperturecommunicating with a cavity within which enzymatic material is disposed;and said respective membranes are disposed within the aperture of therespective outer body element and cooperate therewith to seal eachrespective analyte detector against access to said enzymatic material byliving cells in said tissue.
 46. The sensor of claim 45, wherein each ofsaid plurality of membranes comprise a chemically crosslinkedalbumin-based material.
 47. The sensor of claim 38, wherein saidapparatus configured to promote adaptation of biological tissue of thebody proximate to at least a portion of said plurality of detectorswithout substantive blood vessel ingrowth comprises, for each of saidanalyte detectors: an outer body element having at least one apertureformed therein and defining an interior cavity; an enzymatic materialdisposed within the cavity; and a non-enzymatic membrane materialdisposed at least partly within the at least one aperture, thenon-enzymatic material configured to mitigate blood vessel ingrowth andsubstantially prevent migration of one or more hydrogen peroxide speciesfrom said cavity to said biological tissue.
 48. The sensor of claim 47,wherein each of said plurality of detectors comprises an electrochemicalapparatus, and is further configured to electrically insulate thebiological tissue from the electrochemical apparatus during operationvia at least an electrically insulating membrane disposed between atleast the electrochemical apparatus and the biological tissue.
 49. Thesensor of claim 48, wherein the electrically insulating membranedisposed between at least the electrochemical apparatus and thebiological tissue comprises a silicone rubber membrane disposed betweenthe electrochemical apparatus and the biological tissue.
 50. Animplantable analyte sensor, comprising: a biocompatible housing having asize and shape suitable for implantation in a body; a plurality ofenzymatic analyte detectors, each of the plurality of enzymaticdetectors configured to both (i) mitigate foreign body response (FBR) tothe respective detector by biological tissue surrounding at least aportion of the implantable analyte sensor after implantation thereof ina living being, and (ii) mitigate blood vessel ingrowth into thedetector after said implantation; and circuitry operatively connected tothe plurality of detectors and configured to: process at least a portionof signals generated by one or more of the detectors to produceprocessed signals, and generate a composite signal using the processedsignals; at least one data transmission apparatus configured to transmitthe composite signal to a receiver when the implanted sensor is disposedin a tissue environment within said body; and an electrical power sourceoperatively coupled to at least the circuitry and data transmissionapparatus and configured to provide electrical power thereto.
 51. Theimplantable analyte sensor of claim 50, wherein the configuration tomitigate foreign body response (FBR) to the respective detector bybiological tissue surrounding at least a portion of the implantableanalyte sensor after implantation thereof in a living being, comprisesrespective apparatus configured to both mitigate migration of hydrogenperoxide from an enzymatic material containing cavity of each respectivedetector, yet permit adaptation of the biological tissue to at least aportion of a shape of each respective detector.
 52. An implantableanalyte sensor, comprising: a biocompatible housing having a size andshape suitable for implantation in a body; a plurality of analytedetectors configured to generate analyte-modulated signals; circuitryoperatively connected to the plurality of detectors and configured to:identify one or more of the plurality of analyte detectors which eachexperience unacceptable performance; based at least in part on theidentification, selectively removing signals generated by the identifiedone of more of the plurality of analyte detectors; and process signalsgenerated by remaining, non-identified ones of the plurality of analytedetectors to produce processed signals; one or more data transmissionapparatus configured to transmit at least a portion of said processedsignals to a receiver when the implanted sensor is disposed in a tissueenvironment within said body; and an electrical power source operativelycoupled to at least the circuitry and data transmission apparatus andconfigured to provide electrical power thereto.
 53. The implantableanalyte sensor of claim 52, wherein said sensor is further configured tonot stimulate blood vessel vascularization at least proximate to saidplurality of detectors, yet permit diffusion of said analyte into saidplurality of detectors.
 54. The implantable analyte sensor of claim 52,wherein said processed signals comprise data indicative of one or moreblood glucose concentration values.
 55. The implantable analyte sensorof claim 52, wherein said identification of one or more of the pluralityof analyte detectors which each experience unacceptable performancecomprises identification of one or more of the plurality of analytedetectors which experience unacceptable performance due to foreign bodyresponse (FBR) to the one or more detectors over a period of time. 56.The implantable analyte sensor of claim 52, wherein said identificationof one or more of the plurality of analyte detectors which eachexperience unacceptable performance comprises identification of one ormore of the plurality of analyte detectors which experience unacceptablevariation or one or more parameters relative to a prescribed metric. 57.A method of extending the in vivo operating lifetime of an implantedanalyte sensing device within a living host while also maintaining itsoperability, the method comprising: enabling a tissue response to saidimplanted analyte sensing device such that tissue of the living hostproximate the implanted analyte sensing device substantially interlockswith a sensing feature of the implanted analyte sensing device, whereinsaid substantial interlock with said sensing feature provides mechanicalstability to said sensor so as to maintain said position andorientation, and wherein the sensing feature comprises a plurality ofblood analyte-modulated detectors; frustrating vascularization of saidtissue into said sensing feature to limit a number of detectors thatexperience signal variations of the plurality of blood analyte-modulateddetectors; identifying the detectors that experience signal variations;and based on the identifying, selectively removing signals generated bythe detectors that experience signal variations from composite signalprocessing.